, 2011), likely explaining the fragmented mitochondria and altered mitochondrial dynamics seen in the disease (Pandey et al., 2010 and Shirendeb et al., 2011). Among diseases in this category, PD stands out, as it is becoming apparent that some genetic forms of the disease may be in essence disorders of mitochondrial quality control. Paradoxically, the history of PD, at least from a genetic/biochemical perspective, pointed away from such a conclusion, as the earliest observations regarding pathogenesis implied a deficiency of complex

I of the respiratory chain as the key culprit. EGFR inhibitor drugs That conclusion was based on the findings that (1) 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a complex I inhibitor similar to rotenone, caused PD-like symptoms, (2) complex I activity was reported to be reduced in PD postmortem

tissues, (3) mutations in complex I subunits, such as nDNA-encoded NDUFV2, were associated with PD (Nishioka et al., 2010), and (4) accumulations of large-scale deletions of mtDNA were found specifically in the substantia nigra of sporadic PD patients (Bender et al., 2006 and Kraytsberg et al., 2006), the signature target region of the brain in this disease (Dauer and Przedborski, 2003). However, a notable challenge to this concept was the failure to find clear evidence of mutations in mtDNA that cause PD (Simon et al., 2010). Moreover, the identification in the last decade of at least a dozen genetic loci STK38 associated with familial Selleckchem PD0332991 PD (Table 2) has changed our perspective dramatically, as many of these gene products are associated with mitochondria but have no obvious or direct connection to OxPhos, and many

of those proteins appear to be involved in quality control. Two of those PD-related proteins may be involved in quality control in an indirect manner. Phospholipase A2, group VI (PLA2G6) (Seleznev et al., 2006) is a mitochondrial lipase that deacetylates cardiolipin and is involved in ER stress and ER-mitochondrial crosstalk via ceramide (Lei et al., 2008). GRB10-interacting GYF protein-2 (GIGYF2) enhances the activation of mitochondrially localized (Deng et al., 2000 and Galli et al., 2009) extracellular signal-regulated kinases ERK1 and ERK2 (Deng et al., 2000 and Higashi et al., 2010), both of which are involved in mitophagy (Dagda et al., 2008b) and apoptosis (Deng et al., 2000 and Higashi et al., 2010). A much stronger case for a role in mitochondrial quality control can be made for Parkin, a cytosolic E3 ubiquitin ligase. However, in this role, Parkin does not act alone, as mounting evidence implicates the necessary interaction with another PD-related and mitochondrially localized protein, PINK1. PINK1 is a kinase of unknown specificity that displays a possible dual location in the organelle, i.e., it has been found in both the outer (Zhou et al., 2008) and inner (Jin et al., 2010 and Silvestri et al., 2005) membranes.